Centenarian controls increase variant effect sizes by an average twofold in an extreme case–extreme control analysis of Alzheimer’s disease
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Abstract
Abstract The detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect-sizes are mostly small. We hypothesized that variant effect-sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3±7.9 years), 1,664 age-matched controls (66.0±6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4±1.3 years). We estimated the effect-size of 29 variants that were previously associated with AD in genome-wide association studies. Comparing extreme AD-cases with centenarian-controls increased the variant effect-size relative to published effect-sizes by on average 1.90-fold ( SE =0.29, p =9.0×10 −4 ). The effect-size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-ε2 (2.2-fold) and APOE - ε4 (2.0-fold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants ( p <0.05) in relatively small samples. The increase in effect-sizes depended mainly on using centenarians as extreme controls: the average variant effect-size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p =6.8×10 −1 ), suggesting that on average the tested genetic variants did not explain the extremity of the AD-cases. Concluding, using centenarians as extreme controls in AD case-controls studies boosts the variant effect-size by on average two-fold, allowing the replication of disease-association in relatively small samples.
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The initial genetic results for P522R and decreased AD risk were replicated by various independent cohorts.
“The initial genetic results were replicated by various independent cohorts (160, 161, 162).”
From The role of PLCγ2 in immunological disorders, cancer, and neurodegeneration (2021) · cites this paper as [161]
The Discussion says this study provides independent replication of previously reported AD-associated variants in a Dutch population. Table 2 reports an association between the PLCG2 variant and AD, consistent with decreased risk, but the paper describes one independent Dutch study—not replication by various independent cohorts. (LLM, conf=0.86)
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Alzheimer’s Disease Genetics: Review of Novel Loci Associated with Disease
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Genetics Contributes to Concomitant Pathology and Clinical Presentation in Dementia with Lewy Bodies
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Carriers of the p.P522R variant in PLCγ2 have a slightly more responsive immune system
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The Effect of Alzheimer’s Disease-Associated Genetic Variants on Longevity
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Cálculo do custo da cesta básica de Vitória da Conquista – BA, no contexto da pandemia do SARS-CoV-2
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Alzheimer Forecast Analysis u sing Machine Learning
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Parkinson\'s Disease Prediction using Machine Learning Methods and Large Amounts of Data
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TREM2 Risk Variants with Alzheimer’s Disease Differ in Rate of Cognitive DeclinePreprint
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CSF proteomic quantitative trait loci mapping reveals genetic insights into Alzheimer’s disease
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Self-citation
- Authors
- Tesi, N., van der Lee, S. J., Hulsman, M., Jansen, I. E., Stringa, N., van Schoor, N., Meijers-Heijboer, H., Huisman, M., Scheltens, P., Reinders, M. J. T., van der Flier, W. M., & Holstege, H.
- Affiliations
- Amsterdam UMC Location University of Amsterdam (NL)
- Amsterdam Neuroscience (NL)
- Amsterdam Public Health (NL)
- Delft University of Technology (NL)
- Corresponding author
- Holstege, Henne
- ORCID
- Venue
- European Journal of Human Genetics
- Published
- 2018-09-26
- Volume
- 27
- Issue
- 2
- Pages
- 244-253
- ISSN
- 1018-4813 (ISSN-L)
- 1476-5438
- PMC
- PMC6336855
- OpenAlex
- W2949491829
- Cited by
- 65
- References
- 54
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 8 · 2023: 11 · 2022: 10 · 2021: 11 · 2020: 13 · 2019: 2 · 2018: 1
- FWCI
- 4.64
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- European Journal of Human Genetics (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, cc-by)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
- VU Research Portal (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Repository (Delft University of Technology) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- ZonMw (733051061)
- Stichting Dioraphte (VSM 14 04 1402)
- Alzheimer Nederland (WE09.2014–03)
- Amsterdam Neuroscience
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- Alzheimer's disease, centenarians, replication of genetic associations, APOE ε4, APOE ε2, PLCγ2, age of onset, genetic loci
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Female, Humans, Male, Middle Aged, Sample Size, Patient Selection, Polymorphism, Single Nucleotide, Control Groups, Genome-Wide Association Study
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